Coste SC, Kesterson RA, Heldwein KA, Stevens SL, Heard AD, Hollis JH et al. Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat Genet 24: 403-409

Departments of Molecular Microbiology and Immunology, Oregon Health Sciences University, Portland, OR, USA.
Nature Genetics (Impact Factor: 29.35). 05/2000; 24(4):403-9. DOI: 10.1038/74255
Source: PubMed


The actions of corticotropin-releasing hormone (Crh), a mediator of endocrine and behavioural responses to stress, and the related hormone urocortin (Ucn) are coordinated by two receptors, Crhr1 (encoded by Crhr) and Crhr2. These receptors may exhibit distinct functions due to unique tissue distribution and pharmacology. Crhr-null mice have defined central functions for Crhr1 in anxiety and neuroendocrine stress responses. Here we generate Crhr2-/- mice and show that Crhr2 supplies regulatory features to the hypothalamic-pituitary-adrenal axis (HPA) stress response. Although initiation of the stress response appears to be normal, Crhr2-/- mice show early termination of adrenocorticotropic hormone (Acth) release, suggesting that Crhr2 is involved in maintaining HPA drive. Crhr2 also appears to modify the recovery phase of the HPA response, as corticosterone levels remain elevated 90 minutes after stress in Crhr2-/- mice. In addition, stress-coping behaviours associated with dearousal are reduced in Crhr2-/- mice. We also demonstrate that Crhr2 is essential for sustained feeding suppression (hypophagia) induced by Ucn. Feeding is initially suppressed in Crhr2-/- mice following Ucn, but Crhr2-/- mice recover more rapidly and completely than do wild-type mice. In addition to central nervous system effects, we found that, in contrast to wild-type mice, Crhr2-/- mice fail to show the enhanced cardiac performance or reduced blood pressure associated with systemic Ucn, suggesting that Crhr2 mediates these peripheral haemodynamic effects. Moreover, Crhr2-/- mice have elevated basal blood pressure, demonstrating that Crhr2 participates in cardiovascular homeostasis. Our results identify specific responses in the brain and periphery that involve Crhr2.

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Available from: Susan Murray, Dec 10, 2014
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    • "The CRHR2 genetic locus 7p21-p15 is also linked to T2D,57,58 glycemia, triglyceride, and HDL levels.59 CRHR2−/− mice show high blood pressure and reduced sustained hypophagia;49 thus CRHR2 variants may lead to high blood pressure and obesity of MetS, the latter potentially due to impaired mediation of food intake control. "
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    ABSTRACT: Depression, type 2 diabetes (T2D), and metabolic syndrome (MetS) are often comorbid. Depression per se increases the risk for T2D by 60%. This risk is not accounted for by the use of antidepressant therapy. Stress causes hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis, by triggering the hypothalamic corticotropin-releasing hormone (CRH) secretion, which stimulates the anterior pituitary to release the adrenocorticotropin hormone (ACTH), which causes the adrenal secretion of cortisol. Depression is associated with an increased level of cortisol, and CRH and ACTH at inappropriately "normal" levels, that is too high compared to their expected lower levels due to cortisol negative feedback. T2D and MetS are also associated with hypercortisolism. High levels of cortisol can impair mood as well as cause hyperglycemia and insulin resistance and other traits typical of T2D and MetS. We hypothesize that HPA axis hyperactivation may be due to variants in the genes of the CRH receptors (CRHR1, CRHR2), corticotropin receptors (or melanocortin receptors, MC1R-MC5R), glucocorticoid receptor (NR3C1), mineralocorticoid receptor (NR3C2), and of the FK506 binding protein 51 (FKBP5), and that these variants may be partially responsible for the clinical association of depression, T2D and MetS. In this review, we will focus on the correlation of stress, HPA axis hyperactivation, and the possible genetic role of the CRHR1, CRHR2, MCR1-5, NR3C1, and NR3C2 receptors and FKBP5 in the susceptibility to the comorbidity of depression, T2D, and MetS. New studies are needed to confirm the hypothesized role of these genes in the clinical association of depression, T2D, and MetS.
    The Application of Clinical Genetics 04/2014; 7:43-53. DOI:10.2147/TACG.S39993
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    • "in regions that promote stress recovery (Bale et al., 2000; Coste et al., 2000), including the LS (Victoria et al. 2013, unpublished data). Given that corticosterone-GR complexes transcriptionally regulate the central expression of CRFRs (Schoneveld et al., 2004), such changes are expected. "
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    ABSTRACT: Less than 60% of infants undergoing invasive procedures in the NICU receive analgesic therapy. These infants show long-term decreases in pain sensitivity and cortisol reactivity. In rats we have previously shown that inflammatory pain experienced on the day of birth significantly decreases adult somatosensory thresholds and responses to anxiety- and stress-provoking stimuli. These long-term changes in pain and stress responsiveness are accompanied by 2-fold increases in central met-enkephalin and ß-endorphin expression. However, the time course over which these changes in central opioid peptide expression occur, relative to the time of injury, are not known. The present studies were conducted to determine if the observed changes in adult opioid peptide expression were present within the first postnatal week following injury. The impact of neonatal inflammation on plasma corticosterone, a marker for stress reactivity, was also determined. Brain, spinal cord and trunk blood were harvested at 24 hrs, 48 hrs and 7 days following intraplantar administration of the inflammatory agent carrageenan on the day of birth. Radioimmunoassay was used to determine plasma corticosterone and met-enkephalin and ß-endorphin levels within the forebrain, cortex, midbrain, and spinal cord. Within 24 hrs of injury met-enkephalin levels were significantly increased in the midbrain, but decreased in the spinal cord and cortex; forebrain ß-endorphin levels were significantly increased as a result of early life pain. Corticosterone levels were also significantly increased. At 7 days post-injury, opioid peptides remained elevated relative to controls, suggesting a time point by which injury induced changes become programmed and permanent. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013.
    Developmental Neurobiology 01/2014; 74(1). DOI:10.1002/dneu.22129 · 3.37 Impact Factor
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    • "Intravenous urocortin 1 causes marked vasodilatation in mice via CRH‐R2.5–6 Furthermore, mice lacking CRH‐R2 receptors are hypertensive, suggesting a role for urocortin in the maintenance of basal vascular tone.6 Systemic administration of urocortin 2 in humans increases cardiac output, heart rate, and left ventricular function while decreasing systemic vascular resistance, and these effects may be amplified in the setting of heart failure.7–8 "
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    ABSTRACT: Urocortin 2 and urocortin 3 are endogenous peptides with an emerging role in cardiovascular pathophysiology. We assessed their pharmacodynamic profile and examined the role of the endothelium in mediating their vasomotor effects in vivo in man. Eighteen healthy male volunteers (23±4 years) were recruited into a series of double-blind, randomized crossover studies using bilateral forearm venous occlusion plethysmography during intra-arterial urocortin 2 (3.6 to 120 pmol/min), urocortin 3 (1.2 to 36 nmol/min), and substance P (2 to 8 pmol/min) in the presence or absence of inhibitors of cyclooxygenase (aspirin), cytochrome P450 metabolites of arachidonic acid (fluconazole), and nitric oxide synthase (L-NMMA). Urocortins 2 and 3 evoked arterial vasodilatation (P<0.0001) without tachyphylaxis but with a slow onset and offset of action. Inhibition of nitric oxide synthase with L-NMMA reduced vasodilatation to substance P and urocortin 2 (P≤0.001 for both) but had little effect on urocortin 3 (P>0.05). Neither aspirin nor fluconazole affected vasodilatation induced by any of the infusions (P>0.05 for all). In the presence of all 3 inhibitors, urocortin 2- and urocortin 3-induced vasodilatation was attenuated (P<0.001 for all) to a greater extent than with L-NMMA alone (P≤0.005). Urocortins 2 and 3 cause potent and prolonged arterial vasodilatation without tachyphylaxis. These vasomotor responses are at least partly mediated by endothelial nitric oxide and cytochrome P450 metabolites of arachidonic acid. The role of urocortins 2 and 3 remains to be explored in the setting of human heart failure, but they have the potential to have major therapeutic benefits. Unique identifier: NCT01096706 and NCT01296607.
    Journal of the American Heart Association 12/2013; 2(1):e004267. DOI:10.1161/JAHA.112.004267 · 4.31 Impact Factor
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